REGENERATIVE MEDICINE: BACKGROUND

Background

• NIH: Process of creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage, or congenital defects. [1]

• Holds potential in addressing donor organ shortage

• Approaches

– Medical devices and artificial organs

– Tissue engineering

– Cellular Therapies

Medical Devices and Artificial Organs

• Bioreactors that contain tissue meant to perform the functions of a normal organ.

• Does not rely on organ donation. Available when you need it.

• Can provide temporary support until more definitive treatment available.– Help to improve preoperative status for organ

transplant

• Decreases patient mobility and independence.• Still in clinical testing phase

Medical Devices and Artificial Organs

• Bioartificial Liver Device (BAL)– Artificial extracorporeal device used in acute liver

failure. [2]

– Bioreactors containing hepatocytes provide both biotransformation and synthetic liver functions. [3]

– Designed to provide continuous liver support allowing time for the native liver to regenerate or to stabilize the patient until transplantation.

– Forty-four percent reduced mortality in acute liver failure cases. [4]

• Bioartificial Pancreas (BAP)– Still in design phase [5,6,7]

Medical Devices and Artificial Organs

Spheroid Reservoir BioartificialLiver (SRBAL), Mayo

Spheroid Reservoir

Extracorporeal Liver Assist Device

Microcapsulated pancreatic islet cells

Tissue Engineering

• Utilizing 3D scaffolds and controlled cellular environment to produce functional tissues and organs for transplant

• Biomaterials.[8]

– Organic vs. synthetic – Biodegradable vs. permanent

• Decellularization/ Recellularization– Stripping an organ of its cells to obtain the scaffold (ECM)– The scaffold is recellularized with the hosts stem cells, organ

function returns.– The recellularized organ is transplanted into host, no

immunosuppression requirements– Still relies on organ donation

Tissue Engineering

• ECM Biomaterials

– Extracted from small intestinal submucosa, dermis, amniotic membrane tissue, cadaveric fascia, and the bladder acellular matrix graft

– Elicits host-tissue response to I) initiate angiogenesis, II)encourage tissue deposition , III) restoration of structure and function specific to the graft site.

Tissue Engineering

• 2006, Dr. Atala – Engineered urinary bladders for spina bifida patients[9]

• 2008, Prof. Macchiarini – Tissue engineered tracheal transplant[10]

• 2008, Dr. Wolf and Cpl. Isaias Hernandez –Regenerated thigh muscles[11]

• 2011, Dr. Atala – Human kidney created with a 3D bioprinter in 7 hours. [12]

• 2011, Dr. Taylor – Decell/Recell of human heart

Tissue Engineering

Carbon Nanotube Extracellular Matrix Sheets

Mouse Liver DecellularizedHuman Heart

Decellularization with Detergent InfusionCpl. Isaias Hernandez

Cellular Therapies

• Use of autologous, allogeneic or xenogeneic cells that have been manipulated or altered ex vivo

• Stimulating endogenous stem cell populations to mobilize, differentiate, repair, and heal.

• Method of delivery typically involves placing stem cells at site of injury or IV injection.

• Does not necessarily rely on organ donation• Stem cell mechanisms of action still unknown,

lengthy production time, and cost constraints still need to be addressed

Cellular Therapies

• Many clinical trials ongoing [13]

• Adoptive immunotherapy: Pancreatic cancer vaccine (phase 2) [14]

• Epicortical stimulation with EGF of endogenous NPC (preclinical) [15]

• Spinal cord injections for ALS (phase 2) [16]

• Stem cell infusion for patients with MS (phase 3) [17]

• iPSC derived functional liver buds (preclinical) [18]

• Infusion of neural crest stem cells migrate to cardiac infarct zone (preclinical) [19]

REGENERATIVE MEDICINE: MESENCHYMAL STEM CELLS

Mesenchymal Stem Cells

• Mesenchymal stem cells (MSC) are multipotent stromal cells

• Isolated from adipose, BM, umbilical cord, dental pulp.

• Human MSC are actively being researched in clinical trials

• Morphologically, MSC resemble fibroblasts. – Certain criteria have been developed to properly

identify MSC

Mesenchymal Stem Cells

• International Society for Cellular Therapy (ISCT) Minimum criteria [20]

– I - Cells adhere to plastic under standard culture conditions

– IIa - Positive CD105, CD73, and CD90.

– IIb - Negative CD34, CD45, CD11a, CD11b, CD19 or CD79a, and HLA-DR

– III - Ability to differentiate into osteocytes, adipocytes, and chondrocytes in vitro

Processing of Lipoaspirate and Isolation of Adipose Derived MSC

Mesenchymal Stem Cells

• Have been shown to differentiate into most cell types; adipose, osteoblast, cardiac, neuronal, muscular, hematologic.

• MSC have immunomodulatory effects by secreting cytokines. Other effects?

• Create local immunosuppressive microenvironment (tumorogenic potential?)

• Differences exist between MSC of SQ fat and Visceral Fat, and of BM.

• Techniques of differentiation Involve adenoviral vectors (pro-inflammatory)

REGENERATIVE MEDICINE: BARIATRICS

Obesity

• Prevalence of obesity increasing worldwide, mainly in the industrialized nations– U.S. data; Adults (36%), children/adolescents

(16.9%)[21]

• Obesity is expensive.– annual cost of managing obesity in the U.S.

approximately $190.2 billion per year, or 20.6% of national health expenditures [22]

• Associated with increased morbidity and mortality

Medically Complicated Obesity

• Respiratory - Obstructive sleep apnea (OSA), predisposition to respiratory infections, bronchial asthma, and Pickwickian syndrome (obesity hypoventilation syndrome)

• Malignant - Association with endometrial, prostate, colon, breast, gall bladder, and, possibly, lung cancer

• Psychological - Social stigmatization and depression• Cardiovascular - Coronary artery disease (CAD),

essential hypertension, left ventricular hypertrophy, cor pulmonale, obesity-associated cardiomyopathy, accelerated atherosclerosis, and pulmonary hypertension of obesity

• Central nervous system (CNS) - Stroke, idiopathic intracranial hypertension, and meralgia paresthetica

• Obstetric and perinatal - Pregnancy-related hypertension, fetal macrosomia, and pelvic dystocia

• Surgical - Increased surgical risk and postoperative complications, including wound infection, postoperative pneumonia, deep venous thrombosis, and pulmonary embolism

• Pelvic - Stress incontinence• Gastrointestinal (GI) - Gall bladder disease

(cholecystitis, cholelithiasis), nonalcoholic steatohepatitis (NASH), fatty liver infiltration, and reflux esophagitis

• Orthopedic - Osteoarthritis, coxa vera, slipped capital femoral epiphyses, Blount disease and Legg-Calvé-Perthes disease, and chronic lumbago

• Metabolic -Type 2 diabetes mellitus, prediabetes, metabolic syndrome, and dyslipidemia

• Reproductive - In women: Anovulation, early puberty, infertility, hyperandrogenism, and polycystic ovaries; in men: hypogonadotropic hypogonadism

• Cutaneous - Intertrigo (bacterial and/or fungal), acanthosis nigricans, hirsutism, and increased risk for cellulitis and carbuncles

• Extremity - Venous varicosities, lower extremity venous and/or lymphatic edema

• Miscellaneous - Reduced mobility and difficulty maintaining personal hygiene

Medically Complicated Obesity

• Is there a role for regenerative medicine in bariatrics?

Medically Complicated Obesity

• Two approaches to bariatrics being explored:

I) Understanding Obesity:

• Genetic/epigenetic studies on MSC derived models.

• Drug testing with MSC model.

II) Fat transplants for metabolic effects:

• Favorable results in mouse BAT and SQ adipose transplant into visceral cavity

• No study has yet looked at metabolic effects of human adipose transplant.

Summary

• Regenerative medicine is very promising, can address donor organ shortage.

• Many clinical trials underway.

• A lot is still unknown about stem cells.

• Adipose tissue holds a huge reservoir of MSC with unique functions

• Role of regenerative medicine in bariatric medicine is still uncertain; work in progress.

References• 1. NIH Fact sheet on regenerative medicine. http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=62 nih fact sheet regenerative med• 2. Allen J, Hassanein T, Bhatia S (2001). "Advances in bioartificial liver devices". Hepatology 34 (3): 447–55• 3. Artificial and bioartificial liver devices: present and future. http://www.ncbi.nlm.nih.gov/pubmed/19923348• 4. Demetriou AA, Brown Jr RS, Busuttil RW, et al. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. Ann Surg. 2004;239:660–7.

discussion 667–670.• 5. Design of a Bioartificial Pancreas . https://www.karger.com/Article/FullText/345873• 6. The Bioartificial Pancreas, .Hanuman Medical Foundation. • http://www.hanumanmedicalfoundation.org/type-1-diabetes-research/bioartificial-pancreas.html• 7. Design of a bioartificial pancreas. http://www.ncbi.nlm.nih.gov/pubmed/20683347• 8. Biomaterials in Tissue Engineering. http://www.nature.com/nbt/journal/v13/n6/abs/nbt0695-565.html• 9. Tissue-engineered autologous bladders for patients needing cystoplasty. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)68438-9/fulltext• 10. Clinical transplantation of a tissue-engineered airway. http://www.sciencedirect.com/science/article/pii/S0140673608615986• 11. Regenerative medicine of the trachea: the first human case. http://www.ncbi.nlm.nih.gov/pubmed/16042099• 12. Hill, David. "GROWING HUMAN ORGANS — DR. ANTHONY ATALA BLOWS THE MINDS OF A TED AUDIENCE." N.p., 2012. Web. 30 Mar. 2013.

<http://singularityhub.com/2011/03/15/growing-human-organs-%E2%80%94-dr-anthony-atala-blows-the-minds-of-a-ted-audience/>.• 13. Clinical Trials search engine. http://clinicaltrials.gov/ct2/home• 14. A Lethally Irradiated Allogeneic Granulocyte-Macrophage Colony Stimulating Factor-Secreting Tumor Vaccine for Pancreatic Adenocarcinoma: A Phase II Trial of Safety, Efficacy, and

Immune Activation. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085934/• 15 Controlled epi-cortical delivery of epidermal growth factor for the stimulation of endogenous neural stem cell proliferation in stroke-injured brain.

http://www.ncbi.nlm.nih.gov/pubmed/21550655• 16 Emory Stem Cell Trial. http://www.neurology.emory.edu/ALS/Support%20Our%20Center/active_trials/stem_cell_trial.html• 17Stem Cell Therapy for Patients With Multiple Sclerosis Failing Alternate Approved Therapy- A Randomized Study.

http://www.clinicaltrials.gov/ct2/show/NCT00273364?term=stem+cell&cond=%22Multiple+Sclerosis%22&phase=2&rank=1• 18. Vascularized and functional human liver from an iPSC-derived organ bud transplant. http://www.nature.com/nature/journal/v499/n7459/full/nature12271.html• 19 Neural crest-derived stem cells migrate and differentiate into cardiomyocytes after myocardial infarction.. http://www.ncbi.nlm.nih.gov/pubmed/21212399• 20. Comparative Analysis of Mesenchymal Stromal Cells Biological Properties. http://www.hindawi.com/isrn/sc/2013/674671• 21. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA. Feb 1

2012;307(5):491-7. • 22. Cawley J, Meyerhoefer C. The medical care costs of obesity: an instrumental variables approach. J Health Econ. Jan 2012;31(1):219-30• Nature review, Transplantation of adipose tissue and stem cells: role in metabolism and disease. Thien T. Tran and C. Ronald Kahn. 2010.• Naturally Occurring Scaffolds for Soft Tissue Repair and Regeneration. http://online.liebertpub.com/doi/abs/10.1089/107632702753725058• Heparan Sulfate Proteoglycan Mimetics Promote Tissue Regeneration: An Overview. http://www.intechopen.com/books/tissue-regeneration-from-basic-biology-to-clinical-

application/heparan-sulfate-proteoglycan-mimetics-thrive-tissue-regeneration-an-overview• Organ Donor statistics. http://organdonor.gov/about/data.html• Obesity epidemiology and background. http://emedicine.medscape.com/article/123702-clinical• A Trial of Boost Vaccinations of Pancreatic Tumor Cell Vaccine. http://clinicaltrials.gov/show/NCT01088789• Adipose tissue-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo: advantages over bone marrow-derived mesenchymal stem cells.

http://www.ncbi.nlm.nih.gov/pubmed/20558580